MNX1-AS1 suppresses chemosensitivity by activating the PI3K/AKT pathway in breast cancer.

Abstract

Long noncoding RNAs (lncRNAs) critically regulate tumorigenesis and chemosensitivity. Despite the pivotal role of lncRNAs in breast cancer (BC), their specific functions and underlying mechanism, particularly in the context of drug resistance, remain largely unexplored. We discovered that MNX1-AS1 is significantly elevated in BC and contributes to paclitaxel resistance through the PI3K/AKT pathway. Moreover, elevated MNX1-AS1 expression exhibits close association with unfavourable prognosis in BC. Mechanistically, MNX1-AS1 interacts with YBX1, preventing its SMURF2-mediated ubiquitination and subsequent degradation, thereby increasing YBX1 protein levels. Upregulated YBX1 transcriptionally activates the expression of ITGA6 by binding to its promoter in the nucleus. Furthermore, MNX1-AS1 binds to IGF2BP2, promoting the stability of ITGA6 mRNA in an m6A-dependent manner within the cytoplasm. MNX1-AS1 increases ITGA6 expression at transcriptional and post-transcriptional levels, thereby activating the PI3K/AKT pathway. Notably, lipid nanoparticles were implicated to effectively deliver MNX1-AS1 siRNA to tumor-bearing mice, resulting in significant antitumor effects. These findings underscore the role of MNX1-AS1 in activating the ITGA6/PI3K/AKT pathway, which facilitates tumor progression and induces chemoresistance in BC. Targeting MNX1-AS1 may represent a promosing therapeutic strategy to enhance chemotherapy efficacy in BC patients.